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US5187168A - Substituted quinazolines as angiotensin II antagonists - Google Patents

Substituted quinazolines as angiotensin II antagonists Download PDF

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Publication number
US5187168A
US5187168A US07/782,850 US78285091A US5187168A US 5187168 A US5187168 A US 5187168A US 78285091 A US78285091 A US 78285091A US 5187168 A US5187168 A US 5187168A
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Prior art keywords
alkyl
aralkyl
perfluoroalkyl
alkoxyalkyl
methyl
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Expired - Lifetime
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US07/782,850
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English (en)
Inventor
John L. Primeau
Lloyd M. Garrick
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Wyeth LLC
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American Home Products Corp
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Priority to US07/782,850 priority Critical patent/US5187168A/en
Assigned to AMERICAN HOME PRODUCTS CORPORATION A CORP. OF DE reassignment AMERICAN HOME PRODUCTS CORPORATION A CORP. OF DE ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: GARRICK, LLOYD M., PRIMEAU, JOHN L.
Priority to US07/927,032 priority patent/US5236925A/en
Priority to PT100993A priority patent/PT100993B/pt
Priority to AU31227/93A priority patent/AU3122793A/en
Priority to CA002121816A priority patent/CA2121816A1/fr
Priority to JP5507898A priority patent/JPH07500344A/ja
Priority to PCT/US1992/008991 priority patent/WO1993008170A1/fr
Priority to EP92925018A priority patent/EP0612317A1/fr
Publication of US5187168A publication Critical patent/US5187168A/en
Application granted granted Critical
Priority to US08/034,030 priority patent/US5256781A/en
Assigned to WYETH reassignment WYETH CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: AMERICAN HOME PRODUCTS CORPORATION
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the compounds described in this invention as well as their non-toxic salts and pharmaceutical compositions containing them are useful for the treatment of hypertension and congestive heart failure. These compounds are also useful as lipid lowering agents.
  • the renin-angiotensin system plays a well-defined role in cardiovascular homeostasis [Ocain, T. D. et al. (1991) Drugs of the Future 16, 37-51].
  • Angiotensinogen is converted to angiotensin I by the enzyme renin.
  • Angiotensin I is then acted upon by angiotensin converting enzyme (ACE) to form Angiotensin II (A II).
  • ACE angiotensin converting enzyme
  • a II possesses many crucial properties including vasoconstriction, aldosterone release, and water retention and is implicated as the cause of high blood pressure in a number of species including man.
  • ACE angiotensin converting enzyme
  • a II possesses many crucial properties including vasoconstriction, aldosterone release, and water retention and is implicated as the cause of high blood pressure in a number of species including man.
  • These hypertensive responses are the result of A II acting at specific receptor sites. Compounds
  • non-peptidic amino substituted nitrogenous 6 membered heterocycles fused to 5 or 6 membered aromatic rings are either oxo-quinazolines, quinoline ethers, benzimidazoles, fused heterocyclic imidazoles or oxo-pyrimidines.
  • This invention describes the composition and utility of novel heterocycles of the general formula I: ##STR2## wherein A is O, S, NR 6 , --CR 7 ⁇ CR 8 --;
  • Z is O, S, NR 6 , --CR 7 ⁇ CR 8 --;
  • X is H, NR 9 R 10 , OR 11 , CN, F, Cl, I, Br, perfluoroalkyl, alkyl, alkoxy, alkyl-OH, alkoxyalkyl, --(CH 2 ) n CO 2 R 11 , --(CH 2 ) n CONR 9 R 10 ;
  • R 1 is 5-tetrazolyl, CO 2 R 11 , SO 3 H, NHSO 2 CH 3 , NHSO 2 CF 3 ;
  • R 2 , R 3 , R 4 , R 7 , R 8 is H, alkyl, alkoxy, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl, CN, NO 2 , SO 2 R 13 , --(CH 2 ) n CO 2 R 11 , --(CH 2 ) n CONR 9 R 10 , OR 11 , F, Cl, Br, I, NR 9 R 10 ;
  • R 5 is alkyl, alkoxy, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl, H, --CN, NO 2 , SO 2 R 13 , --(CH 2 ) n CO 2 R 11 , --(CH 2 ) n CONR 9 R 10 , --OH, OR 11 , F, Cl, Br, I, NR 9 R 10 ;
  • R 5 is alkyl, alkoxy, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl, H, --CN, NO 2 , SO 2 R 13 , --(CH 2 ) n CO 2 R 11 ,
  • R 6 is H, alkyl, aralkyl
  • R 9 , R 10 is H, alkyl, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl;
  • R 11 is H, alkyl, aralkyl, alkoxyalkyl
  • R 12 , R 14 is H, alkyl, alkoxy, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl, CN, NO 2 , SO 2 R 13 , (CH 2 ) n CO 2 R 11 , --(CH 2 ) n CONR 9 R 10 ;
  • R 13 is H, OR 11 , alkyl, perfluoroalkyl, aralkyl, --(CH 2 ) n CO 2 R 11 , --(CH 2 ) n CONR 9 R 10 ;
  • n 0, 1, 2 or 3;
  • alkyl is defined as 1-8 carbons, branched or straight chain; perfluoroalkyl is defined as 1-6 carbons; aralkyl is defined as 7-12 carbons or 7-12 carbons substituted with fluorine, bromine or chlorine and the pharmaceutically acceptable salts thereof.
  • a preferred aspect of the present invention are the compounds represented by the general formula I wherein:
  • A is S, --CR 7 ⁇ CR 8 --;
  • Z is S, --CR 7 ⁇ CR 8 --;
  • X is H, CN, F, Cl, perfluoroalkyl, alkyl, alkyl-OH, alkoxyalkyl, --(CH 2 ) n CO 2 R 11 , (CH 2 ) n CONR 9 R 10 ;
  • R 1 is 5-tetrazolyl, CO 2 H, SO 3 H, NHSO 2 CF 3 ;
  • R 2 , R 3 , R 4 , R 7 , R 8 H, alkyl, alkoxy, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl, CN, NO 2 , SO 2 R 13 , --(CH 2 ) n CO 2 R 11 , --(CH 2 ) n CONR 9 R 10 , OR 11 , F, Cl, Br, I, NR 9 R 10 ;
  • R 5 is alkyl, alkoxy, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl, H, --CN, NO 2 , SO 2 R 13 , --(CH 2 ) n CO 2 R 11 , --(CH 2 ) n CONR 9 R 10 , --OH, OR 11 , F, Cl, Br, I, NR 9 R 10 ;
  • R 5 is alkyl, alkoxy, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl, H, --CN, NO 2 , SO 2 R 13 , --(CH 2 ) n CO 2 R 11 , --(CH 2 ) n CONR 9 R 10 ;
  • R 9 , R 10 is H, alkyl, perfluoroalkyl, aralkyl
  • R 11 is H, alkyl, aralkyl, alkoxyalkyl
  • R 12 , R 14 is H, alkyl, alkoxy, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl, CN, NO 2 ;
  • R 13 is H, OR 11 , alkyl, perfluoroalkyl, aralkyl, --(CH 2 ) n CO 2 R 11 , --(CH 2 ) n CONR 9 R 10 ;
  • n 0, 1, 2 or 3;
  • alkyl is defined as 1-8 carbons, branched or straight chain; perfluoroalkyl is defined as 1-6 carbons; aralkyl is defined as 7-12 carbons or 7-12 carbons substituted with fluorine, bromine or chlorine and the pharmaceutically acceptable salts thereof.
  • A is --CR 7 ⁇ CR 8 --, S;
  • X is H, Cl, perfluoroalkyl, alkyl
  • R 1 is 5-tetrazolyl, CO 2 H SO 3 H, NHSO 2 CF 3 ;
  • R 2 , R 3 , R 4 , R 7 , R 8 is H, alkyl, alkoxy, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl, CN, NO 2 , SO 2 R 13 , OR 11 , F, Cl, Br, I, NR 9 R 10 ;
  • R 5 is alkyl, alkoxy, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl, H, --CN, NO 2 , SO 2 R 13 , --OH, OR 11 , F, Cl, Br, I, NR 9 R 10 ;
  • R 5 is alkyl, alkoxy, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl, H, --CN, NO 2 , SO 2 R 13 ;
  • R 9 , R 10 is H, alkyl, perfluoroalkyl, aralkyl
  • R 11 is H, alkyl, aralkyl, alkoxyalkyl
  • R 12 , R 14 is H, alkyl, alkoxy, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl;
  • R 13 is H, OR 11 , alkyl, perfluoroalkyl, aralkyl;
  • n 0, 1, 2 or 3;
  • alkyl is defined as 1-8 carbons, branched or straightchain; perfluoroalkyl is defined as 1-6 carbons; aralkyl is defined as 7-12 carbons or 7-12 carbons substituted with fluorine, bromine or chlorine and the pharmaceutically acceptable salts thereof.
  • the compounds of general formula 1 can be prepared as described in scheme 1.
  • the 4-chloroquinazoline 2 can be reacted with the aminomethylbiphenyl 3 in the presence of a base such as sodium acetate or potassium carbonate in tetrahydrofuran or tetrahydrofuran/dioxane at room temperature to reflux.
  • compounds 4 can be prepared as shown in scheme 2.
  • the bromophenylquinazolines 5 can be prepared by reacting the 4-chloroquinazoline with p-bromobenzylamine, followed by protection of the benzylic nitrogen with a suitable protecting group as described by T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1981. Conversion of 5 to its Grignard reagent, followed by the reaction of this with the oxazoline shown using the procedure of A. I. Meyers, et. al., J. Am. Chem. Soc., 97, 7383, 1975, yields 6.
  • DMA dimethylaniline
  • the thienopyrimidine compounds 12 are prepared as shown in scheme 5 using the same reaction conditions as those described in scheme 1. ##STR12## wherein R 1 , R 4 and X are as defined above.
  • the compounds of this invention may also form salts with inorganic or organic bases. Any pharmaceutically acceptible salts of these compounds are within the scope of this invention. These salts may be, but are not limited to, ammonium salts, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium, dicyclohexylamine salts, TRIS salts, and salts of amino acids. These compounds may also be converted to N-oxides by treatment with hydrogen peroxide by conventional means.
  • the present invention also provides a pharmaceutical composition which comprises a compound of this invention and a pharmaceutically acceptable carrier.
  • the present invention provides an anti-hypertensive pharmaceutical composition which comprises an antihypertensive effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
  • compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration for patients suffering from heart failure.
  • a composition of the invention is in the form of a unit dose.
  • Suitable unit dose forms include tablets, capsules and powders in sachets or vials.
  • Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 1 to 50 mg.
  • the compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg.
  • Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
  • the compounds may also be administered in a parenteral dosing form.
  • compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and the like. They are formulated in conventional manner, for example, in a manner similar to that used for known antihypertensive agents, diuretics, b-blocking agents or ACE inhibitors.
  • the present invention further provides a compound of the invention for use as an active therapeutic substance.
  • Compounds described in this invention are of particular use in the treatment of hypertension. They can also be used for the treatment of congestive heart-failure.
  • the compounds of this invention also have therapeutic utility in the treatment of hyperlipidemia, and/or hypercholesterolemia.
  • the present invention further provides a method of treating hypertension in mammals including man, which comprises administering to the afflicted mammal an antihypertensive effective amount of a compound or a pharmaceutical composition of the invention.
  • Rats are anesthetized with Dial-Urethane (0.60 mL/kg, ip) and the trachea cannulated with PE 240. Either one femoral artery and both femoral veins or the carotid artery and the corresponding jugular vein are cannulated with PE 50. If the jugular vein is cannulated, two cannulas are placed in the one vein. The initial portion of the duodenum (just distal to the stomach) is cannulated with PE 50 via a small midline incision.
  • MAP mean arterial pressure
  • heart rate is measured from the arterial cannula. Ten to 15 min are allowed following surgery for stabilization of arterial pressure.
  • Ganglion blockade is then produced by intravenous administration of mecamylamine at 3 mg/kg (1 mL/kg of a 3 mg/mL solution). Ganglion blockade causes a fall in arterial pressure of about 50 mmHg. Mecamylamine is given every 90 min throughout the remainder of the experiment.
  • An A II infusion is then begun into the other venous cannula at 0.25 mg/kg/min (at 9.6 uLmin). The A II infusion returns arterial pressure to or slightly above the control level. Once arterial pressure has stabilized with the A II infusion, baseline values for mean arterial pressure (MAP) and heart rate are taken.
  • MAP mean arterial pressure
  • test compound suspended in methyl cellulose
  • the test compound is then administered via the duodenal cannula at 0.1, 3 or, 30 mg/kg in a volume of 1 mL/kg.
  • Mean arterial pressure and heart rate values are tabulated at 15, 30, 60, 90, 120, 150, 180, 210, and 240 min after administration of the test compound.
  • the product of Example 36 administered at 10 mg/kg id lowered the A II dependent blood pressure by an average of 45% one half hour post-administration.
  • the compounds of this invention are effective A II antagonists and therefore are useful for treating hypertension. They are also of value in the management of acute and chronic congestive heart failure, primary and secondary pulmonary hyperaldosteronism, secondary hyperaldosteronism, primary and secondary pulmonary hypertension, hypertension associated with oral contraceptive use, vascular disorders such as migraine, Raynaud's disease, luminal hyperplasia and the atherosclerotic process, renal diseases or renal complications of other diseases or therapies such as proteinuria, glomerulonephritis, glomerular sclerosis, scleroderma, diabetic nephropathy, end stage renal disease, renal transplant therapy and others.
  • These compounds will also be useful in the treatment of left ventricular dysfunction, diabetic retinopathy, Alzheimers disease, in the enhancement of cognition, in treatment of elevated intraoccular pressure, and in the enhancement of retinal blood flow. These compounds will also be useful as antidepressants and anxiolytics and in the prevention or treatment of restenosis following angioplasty. The application of the compounds of this invention for these and similar disorders will be apparent to those skilled in the art.
  • Drug solublized in vehicle (0.1 mL; olive oil, corn oil, 2% Tween 80, or carboxymethyl cellulose) is administered orally through a dosing needle immediately prior to (9:00 AM) and immediately following the 4 h feeding period. Dosing with drugs and feeding of the cholesterol/cholic acid diet is repeated for 4 days. On the morning of the 5th day, rats are sacrificed (decapitation), blood is collected and the livers are removed, weighed and stored frozen (-80° C.). The animals are analyzed for total plasma cholesterol (TPC), high density lipoprotein cholesterol (HDLC, Sigma kit) and triglycerides (TG) on an Abbott Autoanalyzer. VLDL+LDL cholesterol is calculated by the difference between total and HDL cholesterol. HDL cholesterol/total cholesterol is also calculated. Typically the compounds of this invention show a 50% drop in total cholesterol at doses in the range of 100-200 mg/kg.
  • TPC total plasma cholesterol
  • HDLC high density lipoprotein cholesterol
  • TG triglycer
  • the compounds of this invention are effective lipid lowering agents and therefore are useful for treating hyperlipidemia and/or hypercholesterolemia.
  • Part A The preparation of 4-chloro-2-nitrobenzamide.
  • Part B The preparation of 4-chloro-2-aminobenzamide.
  • Part C The preparation of 7-chloro-2-trifluoromethyl-4-quinazalone.
  • Trifluoroacetamide (1.64 g) and 4-chloro-2-aminobenzamide (1.65 g) were mixed intimately and were heated under nitrogen to 180° C. for 4 hours.
  • the reaction solution was cooled to room temperature and solidified.
  • the resulting solid was recrystalized from absolute ethanol to yield 0.51 g (21%) of the product as a buff powder:
  • Part D The preparation of 4,7-dichloro-2-trifluoromethylquinazoline.
  • Part E The preparation of 4'-[[(7-chloro-2-trifluoromethyl-4-quinazolinyl)amino]methyl][1,1'-biphenyl]-2-carboxylic acid.
  • Part B The preparation of 6-chloro-2,4-quinazoline-dione.
  • Part C The preparation of 2,4,6-trichloroquinazoline.
  • Part D The preparation of 4'-[[(2,6-dichloro-4-quinazolinyl)amino]methyl][1,1'-biphenyl]-2-carboxylic acid methyl ester.
  • Part A The preparation of 2-trifluoromethyl-4-quinazolone.
  • Part B The preparation of 4-chloro-2-trifluoromethyl quinazoline.
  • Part C The preparation of N-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-2-trifluoromethyl-4-quinazolinamine.
  • Part A The preparation of 2,4-thieno[3,2-d]pyrimidinedione.
  • Part B The preparation of 2,4-dichloro thieno[3,2-d]pyrimidine.
  • Phosphorous oxychloride 15 mL was added to 1.95 g of 2,4-thieno[3,2-d]pyrimidindione.
  • Dimethylaniline (1 mL) was added and the reaction mixture was heated to reflux for 41/2 hours. After cooling to room temperature, the reaction mixture was quenched into a 0° C. mixture of diethyl ether and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to yield the product. As a brown/yellow solid (1.7 g, 71%).
  • Part C The preparation of 4'-[[[2-chlorothieno-[3,2-d]pyrimidine-4-yl]amino]methyl][1,1'-biphenyl]-2-carboxylic acid methyl ester.
  • Part A The preparation of 2-trifluoromethyl-4-thieno[3,2-d]pyrimidinone.
  • Part B The preparation of 4-chloro-2-trifluoromethylthieno[3,2-d]pyrimidine.
  • Part C The preparation of N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-2-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-amine.
  • Part A The preparation of 4'-nitro(1,1'-biphenyl)-2-carboxylic acid methyl ester.
  • Part B The preparation of 4'-amino(1,1'-biphenyl)-2 carboxylic acid methyl ester.
  • Part C The preparation of 4'-[[2-(pentafluoromethyl)-4-quinazolinyl]amino][1,1'-biphenyl]-2-carboxylic acid methyl ester.

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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
US07/782,850 1991-10-24 1991-10-24 Substituted quinazolines as angiotensin II antagonists Expired - Lifetime US5187168A (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
US07/782,850 US5187168A (en) 1991-10-24 1991-10-24 Substituted quinazolines as angiotensin II antagonists
US07/927,032 US5236925A (en) 1991-10-24 1992-08-06 Fused pyrimidines as angiotensin II antagonists
PT100993A PT100993B (pt) 1991-10-24 1992-10-22 Heterociclos susbstituidos, nomeadamente derivados de quinazolina, processo para a sua preparacao e sua utilizacao
PCT/US1992/008991 WO1993008170A1 (fr) 1991-10-24 1992-10-23 Heterocyles substitues en tant qu'antagonistes de l'angiotensine ii
CA002121816A CA2121816A1 (fr) 1991-10-24 1992-10-23 Heterocycles a substituant comme antagonistes de l'angiotensine ii
JP5507898A JPH07500344A (ja) 1991-10-24 1992-10-23 アンジオテンシン２拮抗物質としての置換ヘテロ環
AU31227/93A AU3122793A (en) 1991-10-24 1992-10-23 Substituted heterocycles as angiotensin ii antagonists
EP92925018A EP0612317A1 (fr) 1991-10-24 1992-10-23 Heterocyles substitues en tant qu'antagonistes de l'angiotensine ii
US08/034,030 US5256781A (en) 1991-10-24 1993-03-22 Substituted quinazolines as angiotensin II antagonists

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US07/782,850 US5187168A (en) 1991-10-24 1991-10-24 Substituted quinazolines as angiotensin II antagonists

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US07/927,032 Division US5236925A (en) 1991-10-24 1992-08-06 Fused pyrimidines as angiotensin II antagonists

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EP (1) EP0612317A1 (fr)
JP (1) JPH07500344A (fr)
AU (1) AU3122793A (fr)
CA (1) CA2121816A1 (fr)
PT (1) PT100993B (fr)
WO (1) WO1993008170A1 (fr)

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US5281603A (en) * 1993-04-23 1994-01-25 American Cyanamid Company Angiotensin II receptor blocking 2,3,6 substituted quinazolinones
US5283242A (en) * 1991-10-24 1994-02-01 American Home Products Corporation Substituted benzimidazoles and quinazolines as antihypertensives
WO1996023777A1 (fr) * 1995-02-01 1996-08-08 University Of Nebraska Board Of Regents Composes synthetiques formant une triple helice
US5658902A (en) * 1994-12-22 1997-08-19 Warner-Lambert Company Quinazolines as inhibitors of endothelin converting enzyme
WO1998025609A1 (fr) * 1996-12-10 1998-06-18 Eli Lilly And Company PYRROLES ACTIFS COMME INHIBITEURS DE sPLA¿2?
US5863917A (en) * 1996-03-01 1999-01-26 Pfizer, Inc. Quinoxaline derivatives useful in therapy
US6084095A (en) * 1994-01-25 2000-07-04 Warner-Lambert Company Substituted pyrido[3,2-d]pyrimidines capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US20020042409A1 (en) * 2000-06-06 2002-04-11 Luzzio Michael Joseph Thiophene derivatives useful as anticancer agents
US6492383B1 (en) 1997-11-11 2002-12-10 Pfizer Inc. Thienopyrimidine and thienopyridine derivatives useful as anticancer agents
US6596726B1 (en) 1994-01-25 2003-07-22 Warner Lambert Company Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US20030162795A1 (en) * 1998-10-22 2003-08-28 Pfizer Inc. Thienopyrimidine and thienopyridine derivatives useful as anticancer agents
US20060035908A1 (en) * 2004-07-16 2006-02-16 Willard Lew Thienopyrimidines useful as Aurora kinase inhibitors
US20060129745A1 (en) * 2004-12-11 2006-06-15 Gunther Thiel Process and appliance for data processing and computer program product
WO2006111549A1 (fr) * 2005-04-21 2006-10-26 Boehringer Ingelheim International Gmbh Dihydrothienopyrimidines destines au traitement de maladies inflammatoires
US20070027126A1 (en) * 2005-07-29 2007-02-01 Wyeth Cyanopyrrole-sulfonamide progesterone receptor modulators and uses thereof
US20070027201A1 (en) * 2005-07-29 2007-02-01 Wyeth Use of progesterone receptor modulators
US20070208044A1 (en) * 2003-07-03 2007-09-06 Myriad Genetics, Incorporated Compounds and therapeutical use thereof
US20080051398A1 (en) * 2005-01-03 2008-02-28 Myriad Genetics, Inc. Method of treating brain cancer
US20100069383A1 (en) * 2003-07-03 2010-03-18 Myriad Pharmaceuticals, Incorporated Compounds and therapeutical use thereof
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AU3122793A (en) 1993-05-21
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EP0612317A1 (fr) 1994-08-31
PT100993B (pt) 1999-07-30
WO1993008170A1 (fr) 1993-04-29

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